title: Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain.
abstract: A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.
authors.affiliation: Division of Clinical Neurosciences, University of Southampton, Southampton General Hospital, Southampton, UK. D.Boche@soton.ac.uk
authors.forename: D
authors.initials: D
authors.lastname: Boche
authors.forename: E
authors.initials: E
authors.lastname: Zotova
authors.forename: R O
authors.initials: RO
authors.lastname: Weller
authors.forename: S
authors.initials: S
authors.lastname: Love
authors.forename: J W
authors.initials: JW
authors.lastname: Neal
authors.forename: R M
authors.initials: RM
authors.lastname: Pickering
authors.forename: D
authors.initials: D
authors.lastname: Wilkinson
authors.forename: C
authors.initials: C
authors.lastname: Holmes
authors.forename: J A R
authors.initials: JA
authors.lastname: Nicoll
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000209:etiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016233:Immunotherapy, Active / Q000379:methods; D008297:Male; D008578:Meninges / Q000098:blood supply / Q000378:metabolism; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D012995:Solubility
chemical_list: D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)